Devices and methods for delivery of bioactive agents

ABSTRACT

Embodiments of the invention include bioactive agent eluting devices. In an embodiment the invention includes a bioactive agent delivery device including a substrate, a hydrophilic polymer disposed on the substrate, and a substantially amorphous bioactive agent disposed on the surface of the hydrophilic polymer. In an embodiment, the invention includes a method of making a bioactive agent delivery device including depositing a hydrophilic polymer on a substrate forming a hydrophilic surface and depositing a substantially amorphous bioactive agent on the hydrophilic surface. In an embodiment, the invention includes a bioactive agent-eluting catheter including a catheter shaft and an expandable balloon disposed on the catheter shaft. Other embodiments are included herein.

This application claims the benefit of U.S. Provisional Application No.61/173,462, filed Apr. 28, 2009, the contents of which are hereinincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to devices and methods for the delivery ofbioactive agents. More specifically, the present invention relates todevices and methods for the delivery of bioactive agents from thesurface of a hydrophilic polymer.

BACKGROUND OF THE INVENTION

The release of bioactive agents from an implanted medical device hasbeen shown to be beneficial for the function of devices and thetreatment of various medical conditions. For example, delivery of abioactive agent from a device can prevent cellular responses initiatedby the presence of the implantable device. Bioactive agents releasedfrom the device can also prevent conditions that would otherwise shortenthe functional life of the device following implantation. A bioactiveagent released from the device may also be directed at treating adiseased area of the body.

SUMMARY OF THE INVENTION

Embodiments of the invention include bioactive agent eluting devices. Inan embodiment the invention includes a bioactive agent delivery deviceincluding a substrate, a hydrophilic polymer disposed on the substrate,and a substantially amorphous bioactive agent disposed on the surface ofthe hydrophilic polymer.

In an embodiment, the invention includes a method of making a bioactiveagent delivery device including depositing a hydrophilic polymer on asubstrate forming a hydrophilic surface and depositing a substantiallyamorphous bioactive agent on the hydrophilic surface.

In an embodiment, the invention includes a bioactive agent-elutingcatheter including a catheter shaft and an expandable balloon disposedon the catheter shaft. A hydrophilic polymer can be disposed on theoutside surface of the balloon and a substantially amorphous bioactiveagent can be disposed on the surface of the hydrophilic polymer.

The above summary of the present invention is not intended to describeeach discussed embodiment of the present invention. This is the purposeof the figures and the detailed description that follows.

BRIEF DESCRIPTION OF THE FIGURES

The invention may be more completely understood in connection with thefollowing drawings, in which:

FIG. 1 is a schematic view of a device in accordance with an embodimentherein.

FIG. 2 is a schematic cross-sectional view of a portion of a device inaccordance with an embodiment herein.

FIG. 3 is a graph showing bioactive agent transfer from a balloon to asilicon tube (simulated vessel).

FIG. 4 is a graph showing bioactive agent transfer from a balloon to anex vivo porcine vessel.

While the invention is susceptible to various modifications andalternative forms, specifics thereof have been shown by way of exampleand drawings, and will be described in detail. It should be understood,however, that the invention is not limited to the particular embodimentsdescribed. On the contrary, the intention is to cover modifications,equivalents, and alternatives falling within the spirit and scope of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment the invention includes a method of making a bioactiveagent delivery device. The method can include depositing a hydrophilicpolymer on a substrate forming a hydrophilic surface; and depositing asubstantially amorphous bioactive agent on the hydrophilic surface. Insome embodiments, depositing the hydrophilic polymer on the substratecan include depositing a photo-polymer on the substrate, thephoto-polymer comprising latent photoreactive groups and a hydrophilicbackbone; and applying actinic radiation to the photo-polymer. The useof a photo-polymer can result in formation of covalent bonds between thehydrophilic polymer and substrate leading to a structurally securecoating.

While not intending to be bound by theory, it is believed that releaseof the bioactive agent can be enhanced by preventing the formation of aninterpenetrating network between the hydrophilic polymer and thebioactive agent composition. As described herein, the use of a solventwhen depositing the bioactive agent that does not solvate thehydrophilic polymer can prevent the formation of an interpenetratingnetwork between the hydrophilic polymer and the bioactive agent. By wayof example, if the hydrophilic polymer is strongly water soluble then asolvent (such as a non-polar solvent, depending on the particularhydrophilic polymer) can be used when depositing the bioactive agentwithout formation of an interpenetrating network. In an embodiment, amethod includes the operation of selecting a solvent that does notsolvate the hydrophilic polymer.

Embodiments herein can also include devices, such as devices with anexpandable balloon that can deliver a bioactive agent. In particular,embodiments herein can include expandable balloons including a baselayer of a hydrophilic polymer and top layer of a substantiallyamorphous bioactive agent disposed on the hydrophilic polymer. In someembodiments, the amorphous bioactive agent can be hydrophobic.

Referring now to FIG. 1, a schematic view of an exemplary device isshown in accordance with an embodiment. The device 100 can be, forexample, an angioplasty balloon catheter. However, further examples ofexemplary devices are described in greater detail below. The device 100includes a catheter shaft 102 and a manifold end 105. The device 100also includes an inflatable balloon 104 disposed around the cathetershaft 102. In FIG. 1, the balloon 104 is shown in an inflatedconfiguration. The catheter shaft 102 can include a channel to conveyair through the catheter shaft 102 and to or from the balloon 104, sothat the balloon 104 can selectively go from a deflated configuration tothe inflated configuration and back again.

FIG. 2 shows a schematic cross-sectional view of a portion of the devicein accordance with an embodiment herein. Specifically, FIG. 2 shows across-sectional view of the expandable balloon 104. The expandableballoon 104 can include a substrate 106 having an inner surface 110 andan outer surface 108. A hydrophilic polymer layer 112 (base layer orbase coat) can be disposed on the outer surface 108 of the substrate106. The hydrophilic polymer layer 112 can include a hydrophilic surface113. A substantially amorphous bioactive agent layer (top layer or topcoat) can be disposed on the hydrophilic surface 113 of the hydrophilicpolymer layer 112.

The substrate 106 can be formed from any material, or combination ofmaterials, capable of expanding, and suitable for use within the body.The one or more material(s) can be based on use of the device. In manyembodiments the expandable materials are compliant and flexiblematerials, such as elastomers (polymers with elastic properties).Exemplary elastomers can be formed from various polymers includingpolyurethanes and polyurethane copolymers, polyethylene,styrene-butadiene copolymers, polyisoprene, isobutylene-isoprenecopolymers (butyl rubber), including halogenated butyl rubber,butadiene-styrene-acrylonitrile copolymers, silicone polymers,fluorosilicone polymers, polycarbonates, polyamides, polyesters,polyvinyl chloride, polyether-polyester copolymers, polyether-polyamidecopolymers, and the like. The substrate 106 can be made of a singleelastomeric material, or a combination of materials.

The substrate 106 can have a thickness suitable for the desiredapplication and device. For example, the thickness of the substrate 106can be in the range of about 5 μm to about 100 μm. Exemplary thicknessesfor the walls of catheter balloons are in the range of about 5 μm toabout 20 μm. The actual thickness of the balloon wall may depend on oneor more factors, such as the desired pliability of the balloon, theoverall profile of the balloon on the catheter (low profile devices mayuse thin walled balloons), the pressure rating for the balloon wall, orthe expansion properties of the balloon.

The manufacture of expandable substrates is well known in the art, andany suitable process can be carried out to provide the expandablesubstrate portion of the insertable medical device as described herein.Catheter balloon construction is described in various references, forexample, U.S. Pat. Nos. 4,490,421, 5,556,383, 6,210,364, 6,168,748,6,328,710, and 6,482,348. Molding processes are typically performed forballoon construction. In an exemplary molding process, an extrudedpolymeric tube is radially and axially expanded at elevated temperatureswithin a mold having the desired shape of the balloon. The balloon canbe subjected to additional treatments following the molding process. Forexample, the formed balloon can be subjected to additional heating stepsto reduce shrinkage of the balloon.

Referring back to FIG. 1, the insertable medical device 100 can alsohave one or more non-expandable (or inelastic) portions. For example, ina balloon catheter, the catheter shaft 102 portion can be thenon-expandable portion. The non-expandable portion can be partially orentirely fabricated from a polymer. Polymers include those formed ofsynthetic polymers, including oligomers, homopolymers, and copolymersresulting from either addition or condensation polymerizations. Examplesof suitable addition polymers include, but are not limited to, acrylicssuch as those polymerized from methyl acrylate, methyl methacrylate,hydroxyethyl methacrylate, hydroxyethyl acrylate, acrylic acid,methacrylic acid, glyceryl acrylate, glyceryl methacrylate,methacrylamide, and acrylamide; vinyls such as ethylene, propylene,vinyl chloride, vinyl acetate, vinyl pyrrolidone, vinylidene difluoride,and styrene. Examples of condensation polymers include, but are notlimited to, nylons such as polycaprolactam, polylauryl lactam,polyhexamethylene adipamide, and polyhexamethylene dodecanediamide, andalso polyurethanes, polycarbonates, polyamides, polysulfones,poly(ethylene terephthalate), polydimethylsiloxanes, andpolyetherketone.

The non-expandable portion can also be partially or entirely fabricatedfrom a metal. Metals that can be used in medical articles includeplatinum, gold, or tungsten, as well as other metals such as rhenium,palladium, rhodium, ruthenium, titanium, nickel, and alloys of thesemetals, such as stainless steel, titanium/nickel, nitinol alloys, cobaltchrome alloys, non-ferrous alloys, and platinum/iridium alloys. Oneexemplary alloy is MP35.

Methods of Forming the Hydrophilic Polymer Layer

In some embodiments, a hydrophilic polymer solution is formed bycombining a hydrophilic polymer with a solvent. Exemplary hydrophilicpolymers are described in greater detail below. The hydrophilic polymersolution can then be applied to a suitable substrate, such as anexpandable balloon disposed on a catheter shaft. Many differenttechniques can be used to apply the hydrophilic polymer solution to thesubstrate. By way of example, exemplary techniques can include dropcoating, blade coating, dip coating, spray coating, and the like.Aspects and details of a balloon coating apparatus and method can befound in commonly owned provisional Application having Ser. No.61/188,929, filed on Aug. 14, 2008, and entitled METHOD AND APPARATUSFOR COATING BALLOON CATHETERS (Chappa et al.).

In some embodiments, such as where a photo-polymer is used to form thehydrophilic layer, an actinic radiation application step can beperformed in order to activate latent photoreactive groups on thehydrophilic polymer or on a cross-linker in order to covalently bond thehydrophilic polymer the substrate surface. By way of example, afterapplying the hydrophilic polymer solution to the substrate, the devicecan be subjected to UV exposure at a desirable wavelength for a periodof time.

Hydrophilic Biocompatible Polymers

One class of hydrophilic polymers useful as polymeric materials formatrix formation is synthetic hydrophilic polymers. Synthetichydrophilic polymers that are biostable (i.e., that show no appreciabledegradation in vivo) can be prepared from any suitable monomer includingacrylic monomers, vinyl monomers, ether monomers, or combinations of anyone or more of these types of monomers. Acrylic monomers include, forexample, methacrylate, methyl methacrylate, hydroxyethyl methacrylate,hydroxyethyl acrylate, methacrylic acid, acrylic acid, glycerolacrylate, glycerol methacrylate, acrylamide, methacrylamide,dimethylacrylamide (DMA), and derivatives and/or mixtures of any ofthese. Vinyl monomers include, for example, vinyl acetate,vinylpyrrolidone, vinyl alcohol, and derivatives of any of these. Ethermonomers include, for example, ethylene oxide, propylene oxide, butyleneoxide, and derivatives of any of these.

Examples of polymers that can be formed from these monomers includepoly(acrylamide), poly(methacrylamide), poly(vinylpyrrolidone),poly(acrylic acid), poly(ethylene glycol), poly(vinyl alcohol), andpoly(HEMA). Examples of hydrophilic copolymers include, for example,methyl vinyl ether/maleic anhydride copolymers and vinylpyrrolidone/(meth)acrylamide copolymers. Mixtures of homopolymers and/orcopolymers can be used.

Examples of some acrylamide-based polymers, such aspoly(N,N-dimethylacrylamide-co-aminopropylmethacrylamide) andpoly(acrylamide-co-N,N-dimethylaminopropylmethacrylamide) are describedin example 2 of Applicants' co-pending U.S. Patent Pub. No. 2006/0030669filed Sep. 17, 2004 (Taton et al.). In some embodiments, the hydrophilicpolymer is a vinyl pyrrolidone polymer, or a vinylpyrrolidone/(meth)acrylamide copolymer such aspoly(vinylpyrrolidone-co-methacrylamide). If a PVP copolymer is used, itcan be a copolymer of vinylpyrrolidone and a monomer selected from thegroup of acrylamide monomers. Exemplary acrylamide monomers include(meth)acrylamide and (meth)acrylamide derivatives, such asalkyl(meth)acrylamide, as exemplified by dimethylacrylamide, andaminoalkyl(meth)acrylamide, as exemplified by aminopropylmethacrylamideand dimethylaminopropylmethacrylamide. For example,poly(vinylpyrrolidone-co-N,N-dimethylaminopropylmethacrylamide) isdescribed in example 2 of U.S. Patent Pub. No. 2006/0030669 (Taton etal.).

Photo-Polymers and Cross-Linkers of the Hydrophilic Layer

Embodiments herein can include the use of photo-polymers to form ahydrophilic polymer layer covalently bonded to a desired substrate.Photo-polymers as used herein can include one or more photoreactivegroups covalently bonded to a polymeric backbone. Embodiments herein canalso include the of a photo-reactive cross-linking reagent in order tocovalently bond a hydrophilic polymer layer to a desired substrate.

As such, embodiments herein can include the use of compounds withphotoreactive groups. As used herein, the phrases “latent photoreactivegroup” and “photoreactive group” are used interchangeably and refer to achemical moiety that is sufficiently stable to remain in an inactivestate (i.e., ground state) under normal storage conditions but that canundergo a transformation from the inactive state to an activated statewhen subjected to an appropriate energy source. Photoreactive groupsrespond to specific applied external stimuli to undergo active speciegeneration with resultant covalent bonding to an adjacent chemicalstructure. For example, in an embodiment, a photoreactive group can beactivated and can abstract a hydrogen atom from an alkyl group. Acovalent bond can then form between the compound with the photoreactivegroup and the compound with the C—H bond. Suitable photoreactive groupsare described in U.S. Pat. No. 5,002,582, the disclosure of which isincorporated herein by reference.

Photoreactive groups can be chosen to be responsive to various portionsof actinic radiation. Typically, groups are chosen that can bephotoactivated using either ultraviolet or visible radiation. Suitablephotoreactive groups include, for example, azides, diazos, diazirines,ketones, and quinones. The photoreactive groups generate active speciessuch as free radicals including, for example, nitrenes, carbenes, andexcited states of ketones upon absorption of electromagnetic energy.

In some embodiments, the photoreactive group is an aryl ketone, such asacetophenone, benzophenone, anthrone, and anthrone-like heterocycles(i.e., heterocyclic analogs of anthrone such as those having N, O, or Sin the 10-position), or their substituted (e.g., ring substituted)derivatives. Examples of aryl ketones include heterocyclic derivativesof anthrone, including acridone, xanthone, and thioxanthone, and theirring substituted derivatives. Other suitable photoreactive groupsinclude quinone such as, for example anthraquinone.

The functional groups of such aryl ketones can undergo multipleactivation/inactivation/reactivation cycles. For example, benzophenoneis capable of photochemical excitation with the initial formation of anexcited singlet state that undergoes intersystem crossing to the tripletstate. The excited triplet state can insert into carbon-hydrogen bondsby abstraction of a hydrogen atom (from a polymeric coating layer, forexample), thus creating a radical pair. Subsequent collapse of theradical pair leads to formation of a new carbon-carbon bond. If areactive bond (e.g., carbon/hydrogen) is not available for bonding, theultraviolet light-induced excitation of the benzophenone group isreversible and the molecule returns to ground state energy level uponremoval of the energy source. Photoreactive aryl ketones such asbenzophenone and acetophenone can undergo multiple reactivations inwater and hence can provide increased coating efficiency.

The azides constitute another class of photoreactive groups and includearylazides (C₆R₅N₃) such as phenyl azide and 4-fluoro-3-nitrophenylazide; acyl azides (—CO—N₃) such as benzoyl azide and p-methylbenzoylazide; azido formates (—O—CO—N₃) such as ethyl azidoformate and phenylazidoformate; sulfonyl azides (—SO₂—N₃) such as benzenesulfonyl azide;and phosphoryl azides (RO)₂PON₃ such as diphenyl phosphoryl azide anddiethyl phosphoryl azide.

Diazo compounds constitute another class of photoreactive groups andinclude diazoalkanes (—CHN₂) such as diazomethane anddiphenyldiazomethane; diazoketones (—CO—CHN₂) such as diazoacetophenoneand 1-trifluoromethyl-1-diazo-2-pentanone; diazoacetates (—O—CO—CHN₂)such as t-butyl diazoacetate and phenyl diazoacetate; andbeta-keto-alpha-diazoacetates (—CO—CN₂—CO—O—) such as t-butyl alphadiazoacetoacetate.

Other photoreactive groups include the diazirines (—CHN₂) such as3-trifluoromethyl-3-phenyldiazirine; and ketenes (—CH═C═O) such asketene and diphenylketene.

The polymeric backbone of the photo-polymer can provide desirablephysical properties to the substrate to which it is bonded. In variousembodiments herein, the polymeric backbone is selected so as to providea hydrophilic surface on the substrate. It will be appreciated that manydifferent types of polymeric backbones may provide a hydrophilicsurface. Exemplary polymers can include, but are not limited to,hyaluronic acid, polyvinyl alcohol, polyvinylpyrrolidone, polyethyleneglycol, collagen, chitosan, and the like.

By way of example, methods for the preparation of photo-PVP aredescribed in U.S. Pat. No. 5,414,075. Methods for the preparation ofphoto-polyacrylamide are described in U.S. Pat. No. 6,007,833.

Methods of Depositing the Bioactive Agent

In many embodiments, the bioactive agent is applied from a solution ormixture. The solution or mixture can be formed by combining thebioactive agent and a solvent. Optionally, one or more additives canalso be added to form the bioactive agent solution or mixture. In someembodiments, the bioactive agent solution or mixture can include morethan one bioactive agent. In some embodiments, the bioactive agentsolution or mixture can include more than one solvent.

The solvent can be selected based on the particular hydrophilic polymerused as the base layer or base coat. In some embodiments, the solventselected is one that does not solvate the particular hydrophilic polymerused as the base layer or base coat (e.g., the solvent of the bioactiveagent solution or mixture is not effective as a solvent for thehydrophilic polymer) at temperature and pressure conditions such asstandard room temperature and pressure (e.g., approximately 72 degreesFahrenheit or 22 degrees Celsius and 760 mmHg). Stated alternately, insome embodiments the hydrophilic polymer is not soluble in the solventof the bioactive agent composition. By using a solvent for the bioactiveagent composition that does not solvate the hydrophilic polymer,formation of an interpenetrating network between the hydrophilic polymerand the bioactive agent can be prevented. As such, the bioactive agentcomposition can be disposed on the surface of the hydrophilic polymerwithout penetrating into the hydrophilic polymer in any substantial way.

As an example, if poly(vinylpyrrolidone) is used as the hydrophilicpolymer of the base layer, then a solvent such as ethyl acetate can beused as the solvent for the bioactive agent solution or mixture, becauseit does not serve as a solvent to poly(vinylpyrrolidone). For certainhydrophilic polymers, possible solvents can include, but are not limitedto, nonpolar solvents. It will be appreciated, though, that somehydrophilic polymers may have solubility in some nonpolar solvents.

After the bioactive agent solution or mixture is formed, it can beapplied to the surface of the hydrophilic polymer layer. Many differenttechniques can be used to apply the bioactive agent solution. By way ofexample, exemplary techniques can include drop coating, blade coating,dip coating, spray coating, and the like. After application, theresidual solvent form the bioactive agent solution or mixture can beevaporated off.

Bioactive Agents

The term “bioactive agent,” refers to an inorganic or organic molecule,which can be synthetic or natural, that causes a biological effect whenadministered in vivo to an animal, including but not limited to birdsand mammals, including humans. A partial list of bioactive agents isprovided below. In some embodiments these bioactive agents may be usedalone, in other embodiments these bioactive agents may be used incombination with one another. A comprehensive listing of bioactiveagents, in addition to information of the water solubility of thebioactive agents, can be found in The Merck Index, Thirteenth Edition,Merck & Co. (2001).

It will be appreciated that many of the exemplary bioactive agentslisted below can be formulated in different ways. For example, many (butnot all) of the bioactive agents listed below can exist in bothcrystalline and amorphous forms. In various embodiments herein, thebioactive agents are used in a substantially amorphous form. As usedherein, substantially amorphous shall refer to active agents that are atleast 60% in amorphous form by weight. In some embodiments, amorphousbioactive agents herein can be at least 80% in amorphous form by weight.In some embodiments, amorphous bioactive agents herein can be at least95% in amorphous form by weight. While not intending to be bound bytheory, it believed that delivery in amorphous form can be advantageousin terms of both release kinetics as well as uptake by the tissue at thedelivery site. In various embodiments, the bioactive agent is arelatively hydrophobic active agent. Hydrophobicity of a bioactive agentcan be assessed base on its solubility in water. As used herein,hydrophobic bioactive agents have a water solubility of less than about0.001 mg/ml.

Exemplary bioactive agents can include those falling within one or moreof the following classes, which include, but are not limited to, ACEinhibitors, actin inhibitors, analgesics, anesthetics,anti-hypertensives, anti polymerases, antisecretory agents, antibiotics,anti-cancer substances, anti-cholinergics, anti-coagulants,anti-convulsants, anti-depressants, anti-emetics, antifungals,anti-glaucoma solutes, antihistamines, antihypertensive agents,anti-inflammatory agents (such as NSAIDs), anti metabolites,antimitotics, antioxidizing agents, anti-parasite and/or anti-Parkinsonsubstances, antiproliferatives (including antiangiogenesis agents),anti-protozoal solutes, anti-psychotic substances, anti-pyretics,antiseptics, anti-spasmodics, antiviral agents, calcium channelblockers, cell response modifiers, chelators, chemotherapeutic agents,dopamine agonists, extracellular matrix components, fibrinolytic agents,free radical scavengers, growth hormone antagonists, hypnotics,immunosuppressive agents, immunotoxins, inhibitors of surfaceglycoprotein receptors, microtubule inhibitors, miotics, musclecontractants, muscle relaxants, neurotoxins, neurotransmitters,polynucleotides and derivatives thereof, opioids, prostaglandins,remodeling inhibitors, statins, steroids, thrombolytic agents,tranquilizers, vasodilators, and vasospasm inhibitors.

In some aspects the bioactive agent includes an antiproliferative agent.The antiproliferative agent can be an anti-angiogenesis agent. In someaspects the bioactive agent includes an anti-inflammatory agent. In someaspects the bioactive agent includes a cell response modifier. In someaspects the bioactive agent includes an anti-thrombotic agent. In someaspects the bioactive agent includes an immunosuppressive agent.

Cell response modifiers are chemotactic factors such as platelet-derivedgrowth factor (pDGF). Other chemotactic factors includeneutrophil-activating protein, monocyte chemoattractant protein,macrophage-inflammatory protein, SIS (small inducible secreted)proteins, platelet factor, platelet basic protein, melanoma growthstimulating activity, epidermal growth factor, transforming growthfactor (alpha), fibroblast growth factor, platelet-derived endothelialcell growth factor, insulin-like growth factor, nerve growth factor,vascular endothelial growth factor, bone morphogenic proteins, and bonegrowth/cartilage-inducing factor (alpha and beta). Other cell responsemodifiers are the interleukins, interleukin inhibitors or interleukinreceptors, including interleukin 1 through interleukin 10; interferons,including alpha, beta and gamma; hematopoietic factors, includingerythropoietin, granulocyte colony stimulating factor, macrophage colonystimulating factor and granulocyte-macrophage colony stimulating factor;tumor necrosis factors, including alpha and beta; transforming growthfactors (beta), including beta-1, beta-2, beta-3, inhibin, activin, andDNA that encodes for the production of any of these proteins.

Examples of statins include lovastatin, pravastatin, simvastatin,fluvastatin, atorvastatin, cerivastatin, rosuvastatin, and superstatin.

Examples of steroids include glucocorticoids such as cortisone,hydrocortisone, dexamethasone, betamethasone, prednisone, prednisolone,methylprednisolone, triamcinolone, beclomethasone, fludrocortisone, andaldosterone; sex steroids such as testosterone, dihydrotestosterone,estradiol, diethylstilbestrol, progesterone, and progestins.

The bioactive agent can provide antirestenotic effects, such asantiproliferative, anti-platelet, and/or antithrombotic effects. In someembodiments, the bioactive agent can be selected from anti-inflammatoryagents, immunosuppressive agents, cell attachment factors, receptors,ligands, growth factors, antibiotics, enzymes, nucleic acids, and thelike. Compounds having antiproliferative effects include, for example,actinomycin D, angiopeptin, c-myc antisense, paclitaxel, taxane, and thelike.

Representative examples of bioactive agents having antithromboticeffects include heparin, heparin derivatives, sodium heparin, lowmolecular weight heparin, hirudin, lysine, prostaglandins, argatroban,forskolin, vapiprost, prostacyclin and prostacyclin analogs,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein Iib/IIIa platelet membrane receptor antibody, coproteinIib/IIIa platelet membrane receptor antibody, recombinant hirudin,thrombin inhibitor (such as commercially available from Biogen),chondroitin sulfate, modified dextran, albumin, streptokinase, tissueplasminogen activator (TPA), urokinase, nitric oxide inhibitors, and thelike.

The bioactive agent can also be an inhibitor of the GPIIb-IIIa plateletreceptor complex, which mediates platelet aggregation. GPIIb/IIIainhibitors can include monoclonal antibody Fab fragment c7E3, also knowas abciximab (ReoPro™), and synthetic peptides or peptidomimetics suchas eptifibatide (Integrilin™) or tirofiban (Agrastat™).

The bioactive agent can be an immunosuppressive agent, for example,cyclosporine, CD-34 antibody, everolimus, mycophenolic acid, sirolimus(rapamycin), rapalogs (analogues of rapamycin), tacrolimus, and thelike.

Additionally, the bioactive agent can be a surface adhesion molecule orcell-cell adhesion molecule. Exemplary cell adhesion molecules orattachment proteins, such as extracellular matrix proteins, includefibronectin, laminin, collagen, elastin, vitronectin, tenascin,fibrinogen, thrombospondin, osteopontin, von Willibrand Factor, bonesialoprotein (and active domains thereof), and hydrophilic polymers suchas hyaluronic acid, chitosan and methyl cellulose, and other proteins,carbohydrates, and fatty acids. Other cell-cell adhesion moleculesinclude N-cadherin and P-cadherin and active domains thereof.

Devices

Bioactive agent eluting devices in accordance with embodiments hereincan include those having an expandable portion. In some embodiments, thebioactive agent eluting device can include both an expandable portionand an non-expandable portion. An exemplary device is a ballooncatheter. Balloon catheter constructions are well known in the art andare described in various documents, for example, U.S. Pat. Nos.4,195,637, 5,041,089, 5,087,246, 5,318,587, 5,382,234, 5,571,089,5,776,101, 5,807,331, 5,882,336, 6,394,995, 6,517,515, 6,623,504,6,896,842, and 7,163,523.

The present invention may be better understood with reference to thefollowing examples. These examples are intended to be representative ofspecific embodiments of the invention, and are not intended as limitingthe scope of the invention.

EXAMPLES Example 1 Formation of Bioactive Agent-Eluting Balloon CoatingComposed of Hydrophilic Basecoat and Hydrophobic Amorphous Bioactiveagent (Paclitaxel) Topcoat

A 3.5×15 mm balloon (P/N 50051-004) was obtained from Minnesota Medtec,Inc. The balloon was inflated with minimal pressure to present a smoothsurface.

Poly[vinyl pyrrolidone^(99%)-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide^(1%)] was obtained (PVP-BBA-APMA). This reagent can beprepared as described in U.S. Pat. Nos. 4,973,493; 4,979,959; 5,002,582;5,263,992; and 5,741,551.

N-Acetylatedpoly[acrylamide^(93.6%)-co-sodium-2-acrylamido-2-methylpropanesulfonate^(4.9%)-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide^(0.9%)]-co-methoxypoly(ethylene glycol)₁₀₀₀ monomethacrylate^(0.6%) (percentages are molepercents) was obtained (PA-BBA-APMA-PEG). This reagent can be preparedas described in U.S. Pat. Nos. 4,979,959; 5,263,992; and 5,512,329.

Disodium 4,5-bis[(4-benzoylbenzyl)oxy]-1,3-benzenedisulfonate (DBDS) wasobtained. This reagent can be prepared by combining4,5-Dihydroxylbenzyl-1,3-disulfonate (CHBDS) with4-bromomethylbenzophenone (BMBP) in THF and sodium hydroxide, thenrefluxing and cooling the mixture followed by purification andrecrystallization (also as described in U.S. Pat. No. 5,714,360).

Poly[acrylamide^(96.5%)-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide^(3.5%)]was obtained (PA-BBA-APMA). This reagent can be prepared as described inU.S. Pat. Nos. 4,722,906; 4,973,493; 4,979,959; 5,002,582; 5,263,992;and 5,512,329.

A first basecoat coating solution (PVP-polyvinylpyrrolidone) wasprepared. The solution consisted of PVP-BBA-APMA at 25 mg/ml,PA-BBA-APMA-PEG at 5 mg/ml, polyvinylpyrrolidone (PVP-K90) at 10 mg/ml,and DBDS at 0.25 mg/ml in a solvent of 85% water/15% isopropyl alcohol(v/v). As such, this first basecoat solution included predominantlypolyvinylpyrrolidone as a hydrophilic polymer (though some PA waspresent).

A second basecoat coating solution (PA-polyacrylamide) was prepared. Thesolution consisted of PA-BBA-APMA at 10 mg/ml and DBDS at 0.5 mg/ml in asolvent of 50% water/50% isopropyl alcohol (v/v). As such, this secondbasecoat solution included predominantly polyacrylamide as a hydrophilicpolymer.

A third basecoat coating solution (PA(2)-polyacrylamide) was prepared.The solution consisted of PA-BBA-APMA at 10 mg/ml in a solvent of 50%water/50% isopropyl alcohol (v/v). As such, this third basecoat solutionincluded predominantly polyacrylamide as a hydrophilic polymer.

The basecoat solution was applied to the balloon using a dip coatmethod. Specifically, the balloon was immersed in the base coat coatingsolution with no dwell time. The balloon was then extracted from thesolution at a speed of 0.5 cm/s. The basecoat was then air dried for atleast 10 minutes. The base coat was then UV cured. Specifically thecoated balloon was rotated in front of a Dymax 2000-EC series UV floodlamp with a 400 Watt metal halide bulb for 3 minutes, approximately 20cm from the light source. Some balloons were left uncoated with abasecoat as a control.

A first topcoat solution was prepared by dissolving paclitaxel at aconcentration of about 30-50 mg/ml in a solvent of ethyl acetate. Asecond topcoat solution was prepared by dissolving paclitaxel at aconcentration of about 30-50 mg/ml in a solvent of chloroform.

The topcoat was applied by drop coating. Specifically, a positivedisplacement pipette was used to apply an appropriate volume of topcoatsolution direct to the balloon to achieve a target drug load of 3μg/mm². The balloon was then rotated by hand to evenly distributetopcoat solution over the balloon surface. The paclitaxel was depositedin a form that was amorphous.

Example 2 Bioactive Agent Transfer from Balloon to Simulated Vessel Wall(Silicone Tubing)

Silicone tubing (0.125 inch I.D., 0.188 inch O.D., 0.0315 inch wall) wasobtained from Cole-Parmer Instrument Co. The silicone tubing was cutinto 1.5 inch lengths.

The silicone tubing pieces were placed individually in 4 mL amber glassvial filled with 4 mL of PBS (phosphate buffer saline) pH-7.4, which waspreheated in a water bath to 37° C.

A deflated, folded balloon (prepared as described above) was placed in apreheated (37° C.) 8 mL vial filled with 8 mL of PBS (phosphate buffersaline) pH-7.4 and soaked for 4 minutes. The balloon was slid into theinner lumen of the silicone tube (submerged inside 4 mL vial) andexpanded for 30 seconds at 4 atmospheres air pressure. Balloon pressurewas released and the balloon was removed from the tubing.

The amount of paclitaxel transferred to the wall of the inner lumen ofthe tubing was then determined. Specifically, the tubing was submergedin 4 mL of a mixture (extraction media) of 0.1% glacial acetic acid inmethanol for 24 hours. A 350 μL aliquot of the extraction media wastransferred to a 96 well plate for bioactive agent content measurementby UV (232 nm). The results are shown in FIG. 3. The category ofPA-based basecoat shown in FIG. 3 is inclusive of results obtained withboth the second basecoat and the third basecoat coating solutions.

This example shows that a basecoat composed primarily ofpolyvinylpyrrolidone (PVP) or polyacrylamide (PA) increased the transferof amorphous paclitaxel applied out of ethyl acetate to a simulatedvessel by 81% and 150%, respectively, over a control balloon with nobasecoat. This example further shows that a basecoat composed primarilyof polyacrylamide (PA) increased the transfer of amorphous paclitaxelapplied out of chloroform to a simulated vessel by 106% over a controlballoon with no basecoat. Thus, this example shows that hydrophilicbasecoats can be used to greatly increase the amount of a substantiallyamorphous hydrophobic bioactive agent delivered from a balloon device.

Finally, this example shows that a basecoat composed primarily ofpolyvinylpyrrolidone (PVP) decreased the transfer of amorphouspaclitaxel applied out of chloroform to a simulated vessel by 58% over acontrol balloon with no base coat. While not intending to be bound bytheory, it is believed that this decrease was because chloroform (fromthe bioactive agent composition) serves as an effective solvent to PVPand the PVP base coat formed an interpenetrating network with thepaclitaxel in chloroform solution during the process of applying thebioactive agent top coat.

Example 3 Bioactive Agent Transfer from Balloon to ex-vivo PorcineArtery

Porcine artery was obtained from Pel-Freeze. The porcine artery was cutinto 1.5 inch lengths.

The porcine artery pieces were placed individually in 4 mL amber glassvial filled with 4 mL of PBS (phosphate buffer saline) pH-7.4, which waspreheated in a water bath to 37° C.

A deflated, folded balloon (prepared as described above) was placed in apreheated (37° C.) 8 mL vial filled with 8 mL of PBS (phosphate buffersaline) pH-7.4 and soaked for 4 minutes. The balloon was slid into theinner lumen of the porcine artery (submerged inside 4 mL vial) andexpanded for 30 seconds at 4 atmospheres air pressure. Balloon pressurewas released and the balloon was removed from the tubing.

The amount of paclitaxel transferred to the wall of the inner lumen ofthe artery was then determined. Specifically, the artery was submergedin 4 mL of a mixture of 0.1% glacial acetic acid in methanol for 24hours. The amount of paclitaxel in the extraction media was thendetermined via HPLC. The results are shown in FIG. 4. The category ofPA-based basecoat shown in FIG. 4 is inclusive of results obtained withboth the second basecoat and the third basecoat coating solutions.

This example shows that a basecoat composed primarily of polyacrylamide(PA) increases the transfer of amorphous paclitaxel applied out of ethylacetate to a simulated vessel by 77%. Thus, this example shows thathydrophilic basecoats can be used to greatly increase the amount of asubstantially amorphous hydrophobic bioactive agent delivered from aballoon device.

It should be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to a composition containing “a compound” includes a mixture oftwo or more compounds. It should also be noted that the term “or” isgenerally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

It should also be noted that, as used in this specification and theappended claims, the phrase “configured” describes a system, apparatus,or other structure that is constructed or configured to perform aparticular task or adopt a particular configuration to. The phrase“configured” can be used interchangeably with other similar phrases suchas arranged and configured, constructed and arranged, constructed,manufactured and arranged, and the like.

All publications and patent applications in this specification areindicative of the level of ordinary skill in the art to which thisinvention pertains. All publications and patent applications are hereinincorporated by reference to the same extent as if each individualpublication or patent application was specifically and individuallyindicated by reference. Nothing herein is to be construed as anadmission that the inventors are not entitled to antedate anypublication and/or patent, including any publication and/or patent citedherein.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

Further Embodiments

In an embodiment, the invention includes a bioactive agent deliverydevice including a substrate, a hydrophilic polymer disposed on thesubstrate, and a substantially amorphous bioactive agent disposed on thesurface of the hydrophilic polymer. In an embodiment, the hydrophilicpolymer is covalently bonded to the substrate. In an embodiment, thehydrophilic polymer is covalently bonded to the substrate through thereaction product of a latent photoreactive group. In an embodiment, thesubstrate includes a polymer. In an embodiment, the polymer includes anelastomer. In an embodiment, the amorphous bioactive agent includes ahydrophobic bioactive agent. In an embodiment, the amorphous bioactiveagent includes paclitaxel. In an embodiment, the amorphous bioactiveagent comprises rapamycin. In an embodiment, the hydrophilic polymerselected from the group consisting of poly(acrylamide),poly(methacrylamide), poly(vinylpyrrolidone), poly(acrylic acid),poly(ethylene glycol), poly(vinyl alcohol), poly(HEMA), methyl vinylether/maleic anhydride copolymers, and vinylpyrrolidone/(meth)acrylamide copolymers. In an embodiment, thehydrophilic polymer is poly(acrylamide). In an embodiment, thehydrophilic polymer is poly(vinylpyrrolidone).

In an embodiment, the invention includes a method of making a bioactiveagent delivery device. The method includes depositing a hydrophilicpolymer on a substrate forming a hydrophilic surface and depositing asubstantially amorphous bioactive agent on the hydrophilic surface. Inan embodiment, depositing the hydrophilic polymer on the substrateincludes depositing a photo-polymer on the substrate, the photo-polymercomprising latent photoreactive groups and a hydrophilic backbone; andapplying actinic radiation to the photo-polymer. In an embodiment,depositing a substantially amorphous bioactive agent on the hydrophilicsurface includes mixing the amorphous bioactive agent with a solvent toform an bioactive agent mixture, depositing the bioactive agent mixtureon the hydrophilic surface, and evaporating the solvent. In anembodiment, evaporation is carried out in a manner to preserve theamorphous characteristics of the bioactive agent. In an embodiment, thesolvent for the bioactive agent mixture is selected such that it doesnot solvate the hydrophilic polymer. In an embodiment, the solventincludes ethyl acetate. In an embodiment, the amorphous bioactive agentincludes a hydrophobic bioactive agent. In an embodiment, the amorphousbioactive agent includes paclitaxel. In an embodiment, the hydrophilicpolymer is selected from the group consisting of poly(acrylamide),poly(methacrylamide), poly(vinylpyrrolidone), poly(acrylic acid),poly(ethylene glycol), poly(vinyl alcohol), poly(HEMA), methyl vinylether/maleic anhydride copolymers, and vinylpyrrolidone/(meth)acrylamide copolymers.

In an embodiment, the invention includes a bioactive agent-elutingcatheter including a catheter shaft; an expandable balloon disposed onthe catheter shaft; a hydrophilic polymer disposed on the outsidesurface of the balloon; and a substantially amorphous bioactive agentdisposed on the surface of the hydrophilic polymer. In an embodiment,the hydrophilic polymer is covalently bonded to the substrate. In anembodiment, the hydrophilic polymer is covalently bonded to thesubstrate through the reaction product of a latent photoreactive group.In an embodiment, the substrate includes a polymer. In an embodiment,the polymer is an elastomer. In an embodiment, the amorphous bioactiveagent includes a hydrophobic bioactive agent. In an embodiment, theamorphous bioactive agent includes paclitaxel. In an embodiment, theamorphous bioactive agent includes rapamycin. In an embodiment, thehydrophilic polymer is selected from the group consisting ofpoly(acrylamide), poly(methacrylamide), poly(vinylpyrrolidone),poly(acrylic acid), poly(ethylene glycol), poly(vinyl alcohol),poly(HEMA), methyl vinyl ether/maleic anhydride copolymers, and vinylpyrrolidone/(meth)acrylamide copolymers. In an embodiment, thehydrophilic polymer includes poly(acrylamide). In an embodiment, thehydrophilic polymer includes poly(vinylpyrrolidone).

1. A method of making a bioactive agent delivery device comprising:depositing a hydrophilic polymer on a substrate forming a hydrophilicsurface; and depositing a substantially amorphous bioactive agent on thehydrophilic surface.
 2. The method of claim 1, wherein depositing thehydrophilic polymer on the substrate comprises: depositing aphoto-polymer on the substrate, the photo-polymer comprising latentphotoreactive groups and a hydrophilic backbone; and applying actinicradiation to the photo-polymer.
 3. The method of claim 1, whereindepositing a substantially amorphous bioactive agent on the hydrophilicsurface comprises: selecting a solvent that does not solvate thehydrophilic polymer; mixing the amorphous bioactive agent with theselected solvent to form an bioactive agent mixture; depositing thebioactive agent mixture on the hydrophilic surface; and evaporating thesolvent.
 4. The method of claim 3, wherein depositing the bioactiveagent mixture on the hydrophilic surface does not result in theformation of an interpenetrating network between the hydrophilic polymerand the bioactive agent mixture.
 5. The method of claim 3, wherein theevaporation preserves the amorphous characteristics of the bioactiveagent.
 6. The method of claim 1, wherein selecting a solvent that doesnot solvate the hydrophilic polymer comprises selecting at least onefrom the group consisting of ethyl acetate and chloroform.
 7. The methodof claim 1, the amorphous bioactive agent comprising a hydrophobicbioactive agent.
 8. The method of claim 1, the amorphous bioactive agentcomprising at least one selected from the group consisting ofpaclitaxel, rapamycin, and rapalogs.
 9. The method of claim 1, thehydrophilic polymer selected from the group consisting ofpoly(acrylamide), poly(methacrylamide), poly(vinylpyrrolidone),poly(acrylic acid), poly(ethylene glycol), poly(vinyl alcohol),poly(HEMA), methyl vinyl ether/maleic anhydride copolymers, and vinylpyrrolidone/(meth)acrylamide copolymers.
 10. A bioactive agent deliverydevice comprising: a substrate; a hydrophilic polymer disposed on thesubstrate; and a substantially amorphous bioactive agent compositiondisposed on the surface of the hydrophilic polymer.
 11. The bioactiveagent delivery device of claim 10, the hydrophilic polymer covalentlybonded to the substrate through the reaction product of a latentphotoreactive group.
 12. The bioactive agent delivery device of claim10, the substantially amorphous bioactive agent composition disposed onthe surface of the hydrophilic polymer without penetrating into thehydrophilic polymer.
 13. The bioactive agent delivery device of claim10, the amorphous bioactive agent composition comprising trace amountsof a solvent comprising a compound that does not solvate the hydrophilicpolymer.
 14. The bioactive agent delivery device of claim 10, theamorphous bioactive agent comprising a hydrophobic bioactive agent. 15.The bioactive agent delivery device of claim 10, the hydrophilic polymerselected from the group consisting of poly(acrylamide),poly(methacrylamide), poly(vinylpyrrolidone), poly(acrylic acid),poly(ethylene glycol), poly(vinyl alcohol), poly(HEMA), methyl vinylether/maleic anhydride copolymers, and vinylpyrrolidone/(meth)acrylamide copolymers.
 16. A bioactive agent-elutingcatheter comprising: a catheter shaft; an expandable balloon disposed onthe catheter shaft; a hydrophilic polymer disposed on the outsidesurface of the balloon; and a substantially amorphous bioactive agentdisposed on the surface of the hydrophilic polymer.
 17. The bioactiveagent-eluting catheter of claim 16, the hydrophilic polymer covalentlybonded to the substrate through the reaction product of a latentphotoreactive group.
 18. The bioactive agent-eluting catheter of claim16, the hydrophilic polymer selected from the group consisting ofpoly(acrylamide), poly(methacrylamide), poly(vinylpyrrolidone),poly(acrylic acid), poly(ethylene glycol), poly(vinyl alcohol),poly(HEMA), methyl vinyl ether/maleic anhydride copolymers, and vinylpyrrolidone/(meth)acrylamide copolymers.
 19. The bioactive agent-elutingcatheter of claim 16, the substantially amorphous bioactive agentcomposition disposed on the surface of the hydrophilic polymer withoutpenetrating into the hydrophilic polymer.
 20. The bioactiveagent-eluting catheter of claim 16, the amorphous bioactive agentcomposition comprising trace amounts of a solvent comprising a compoundthat does not solvate the hydrophilic polymer.